1. Reactions of alkyl halides: nucleophilic Substitution and elimination
Dr. Sheppard
CHEM 2412
Fall 2014
McMurry (8th ed.) sections 10.1, , ,
11.12

2. Alkyl Halides Contain F, Cl, Br, or I Widely used in: Structure:
Synthesis (electrophilic carbon and easy functional group transitions)
Solvents (CCl4, CHCl3, CH2Cl2)
Industrial applications
Structure:

3. Properties of Alkyl Halides
Bond strength
Measured by bond dissociation energy
Inversely proportional to bond length
Electronegativity and small size of F keep bonding electrons close
C-F > C-Cl > C-Br > C-I
short long
strong weak
Which C-X bond is easier to break, C-Cl or C-Br?

4. Properties of Alkyl Halides
Polarity
Alkyl halides have substantial dipole moments
Dipole moments depend on:
Electronegativity of X
F > Cl > Br > I
C-X bond length
C-I > C-Br > C-Cl > C-F
Polarizability of electrons (ease of distribution of electron density)
I > Br > Cl > F
Since these trends oppose one another, the trend in molecular dipole moment is not periodic
C-Cl > C-F > C-Br > C-I

5. Summary of Alkyl Halide Properties

6. Reactions of Alkyl Halides
Carbon bonded to X is electron-poor (electrophilic)
Will react with nucleophiles
Nucleophiles are also bases! So, there are two competing reactions:
Substitution
Nucleophile substitutes for X (the leaving group)
Elimination
Nucleophile/base removes H, eliminates HX to yield an alkene

7. Substitution vs. Elimination
How do we know which reaction will occur?
In this chapter:
Mechanisms of substitution
Mechanisms of elimination
Substitution vs. elimination

8. I. Nucleophilic Substitution
Nucleophile substitute for leaving group (X)
Example:
CH3CH2CH2Br + NaOCH3 → CH3CH2CH2OCH3 + NaBr
Leaving group =
Nucleophile =

9. Stereochemistry
When the product has a stereocenter, we must consider stereochemistry
Examples:
How can we explain the observed stereochemistry?
There is more than one possible mechanism
SN2 and SN1 (differ in timing of C-X breaking and C-Nu formation)

10. The SN2 Reaction Bimolecular nucleophilic substitution
Bimolecular = two species (RX and Nu) participate in RDS
Rate = k [RX] [Nu]
Mechanism:
Single step
No intermediates
Bonds broken and made simultaneously (concerted)
Same mechanism as acetylide ion and methyl/primary RX

11. Transition State of SN2 Reaction

12. CH3Br + NaOH →
Products:
Mechanism:

13. SN2 Energy Diagram
One step
Exothermic E
Reaction Coordinate

14. SN2 Stereochemistry
Nucleophile attacks reaction center (electrophilic carbon) from the direction opposite the leaving group
Backside attack
Causes change in configuration
Stereocenter: S ↔ R
Rings: cis ↔ trans
Ex: (S)-2-bromobutane + NaOH

15. SN2 Characteristics Factors influencing the rate of SN2 reaction:
Alkyl halide structure
Nucleophile
Leaving group
Solvent

16. SN2 Characteristics: RX Structure
Steric effects
Nucleophile must have access to reaction center
Access is hindered with bulky substituents

17. SN2 Characteristics: RX Structure
Trends in RX reactivity:
Methyl halide most reactive
Tertiary alkyl halide not likely to react
Branched 1° and 2° alkyl halides react slower than unbranched
Vinyl and aryl halides will not react

18. SN2 Characteristics: Nucleophile
Nucleophile: contains lone pair
Some nucleophile are better than others
Better nucleophile = faster SN2 reaction
Some common nucleophiles:
What trends do you notice relating nucleophilicity and structure?
Poor
Good
Strong
ROH
RCO2H
H2O F
RCO2
RSH
NH3/NR3 Cl Br I HS HO RO CN

19. Trends in Nucleophile Structure
Anions are stronger nucleophiles than neutral molecules
HO > H2O
RO > ROH

20. Trends in Nucleophile Structure
Less stable anions are stronger nucleophiles than more stable anions
RO > RCO2
Generally, nucleophilicity increases down a group
I > Br , Cl > F
Bulky anions are more likely to act as a base, rather than a nucleophile
(CH3)3CO vs. CH3O
base nucleophile

21. Nucleophile Structure
Some common good nucleophiles are also strong bases
HO-
RO-
H2N-
Some common good nucleophiles are weak bases I-
-CN
RCO2-
This will be important later when comparing substitution and elimination

22. SN2 Characteristics: Leaving Group
Better LG = faster reaction
Better LG = more stable anion

23. SN2 Characteristics: Solvent
Dissolves reactants, creates environment of reaction, can affect outcome of reaction
Solvents are either protic or aprotic
Polar protic
H-bond donor
Contain NH or OH
Alcohols, carboxylic acids, amines, water
Polar aprotic
Cannot donate H-bond
Dimethyl sulfoxide (DMSO)
Acetone
Acetonitrile
N,N-Dimethylformamide (DMF)

24. SN2 Characteristics: Solvent
Polar aprotic solvents solvate cations, but not anions
Anions shielded from d+ by methyl groups
Less solvated
More available to react as nucleophiles
Good for SN2!

25. SN2 Characteristics: Solvent
Polar protic solvents solvate both cations AND anions
Anion is well-solvated
Less available to react as nucleophiles
Not good for SN2!

26. SN2 Summary Rates of Reaction (Kinetics):
What is the rate-determining step for the SN2 reaction?
Does the rate of reaction depend on the concentration of alkyl halide only OR both the alkyl halide and nucleophile?
Stereochemistry:
What happens to a stereocenter (chirality center) during the course of this reaction?
Structure of the Alkyl Halide:
List alkyl halide type (1, 2, 3) in order of decreasing ability to undergo this type of substitution reaction. Are there any types of alkyl halides that do not undergo this type of reaction? Why?
Given this order or reactivity, are electronic factors important for this reaction? Why or why not?
Are steric factors important for this reaction? Why or why not?
The Nucleophile:
Is the nature of the nucleophile important for the SN2 reaction? Why or why not?
The Leaving Group:
Rank the leaving groups of alkyl halides (F-, Cl-, Br-, I-) in their ability to “leave.” Why is this trend observed?
The Solvent:
How do polar aprotic solvents and polar protic solvents affect substitution reactions?
What are the best solvents for the SN2 reaction? Why?

27. The SN1 Reaction Unimolecular nucleophilic substitution
Unimolecular = one species (RX) participates in RDS
Rate = k [RX]
Mechanism:
Multiple steps
Carbocation intermediate
C-X bon broken before C-Nu bond formed
Which step is RDS?

28. Mechanism of SN1 Reaction

29. SN1 Energy Diagram

30. SN1 Stereochemistry Racemic mixture Why? Look at intermediate…
50% inversion of configuration
50% retention of configuration
Why? Look at intermediate…

31. (R)-3-chloro-3-methylhexane + NaOAc →
Products:
Mechanism:

32. SN1 Stereochemistry
Sometimes slightly more than one enantiomer is observed
55-60% inversion
40-45% retention
Why? Association of leaving group with carbocation

33. SN1 Characteristics Factors influencing the rate of SN1 reaction:
Alkyl halide structure
Nucleophile
Leaving group
Solvent

34. SN1 Characteristics: RX Structure
Electronic effects
More stable carbocation = faster reaction
Remember carbocation stability

35. SN1 Characteristics: RX Structure
Trends in RX reactivity:
Tertiary alkyl halides most reactive
Primary alkyl halides will not form unless allylic or benzylic

36. SN1 Characteristics: Nucleophile
Nucleophile is not important for SN1 reactions
Not in the rate equation
Even poor nucleophiles are OK for SN1
H2O, ROH, etc.

37. SN1 Characteristics: Leaving Group
Better LG = faster reaction

38. SN1 Characteristics: Leaving Group
SN1 on alcohols
Need strong acid to protonate –OH and form a better LG

39. SN1 Characteristics: Solvent
Polar protic solvents = faster reaction
Solvate both cations AND anions
Speed up RDS by solvating and separating carbocation intermediate and leaving group anion
Good for SN1!
Commonly SN1 nucleophile = solvent
Solvolysis reaction

40. SN1 Summary Rates of Reaction (Kinetics):
What is the rate-determining step for the SN1 reaction?
Does the rate of reaction depend on the concentration of alkyl halide only OR both the alkyl halide and nucleophile?
Stereochemistry:
What happens to a stereocenter (chirality center) during the course of this reaction?
Structure of the Alkyl Halide:
List alkyl halide type (1, 2, 3) in order of decreasing ability to undergo this type of substitution reaction. Are there any types of alkyl halides that do not undergo this type of reaction? Why?
Given this order or reactivity, are electronic factors important for this reaction? Why or why not?
Are steric factors important for this reaction? Why or why not?
The Nucleophile:
Is the nature of the nucleophile important for the SN1 reaction? Why or why not?
The Leaving Group:
Rank the leaving groups of alkyl halides (F-, Cl-, Br-, I-) in their ability to “leave.” Why is this trend observed?
The Solvent:
How do polar aprotic solvents and polar protic solvents affect substitution reactions?
What are the best solvents for the SN1 reaction? Why?

41. Rearrangements possible
Summary of SN2 vs. SN1
SN2
SN1
Driving force
Steric factors
Electronic factors
Alkyl halide
Methyl 1° 2°
Allylic
Benzylic 3°
Stereochemistry
100% inversion
Racemic mixture
Regiochemistry
No rearrangements
Rearrangements possible
Nucleophile
Good
Good or poor
Solvent
Aprotic
Protic

42. Predict the substitution mechanism and products for the following reactions…

43. Carbocation Rearrangements
Carbocation intermediates can rearrange to form a more stable carbocation structure
Types of rearrangements:
Hydride shift
Alkyl shift (methyl or phenyl)
Can SN2 reactions undergo rearrangement?

44. Draw the Mechanism…

45. Outline In this chapter: Mechanisms of substitution
SN2
SN1
Mechanisms of elimination E2 E1
Substitution vs. elimination

46. II. Elimination Reactions
Alkyl halide + base → alkene
X eliminated from one carbon
H eliminated from adjacent carbon
Compete with substitution reactions

47. 1-Bromobutane + t-BuOK →

48. Elimination Regiochemistry
Multiple products can be formed if there is more than one adjacent H
How do we know the major product?

49. Zaitsev’s Rule
In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates
This alkene is more stable
There are some exceptions, but this rule is generally true
Example:
Which product is major?

50. The E2 Reaction Bimolecular elimination Rate = k [RX] [Base]
Mechanism:
Single step
Concerted
No intermediates
Needs a strong base (NaOH, NaOR, NaNH2)

51. E2 Stereochemistry The alkyl halide must have anti-periplanar geometry
Anti = H and X on opposite sides of molecule
Less steric strain between base and leaving group
Periplanar = all 4 reacting atoms (H, C, C, X) are in the same plane
Maximizes molecular orbital overlap in transition state

52. What is the major product of E2 reaction of (2S,3R)-2-bromo-3-methylpentane

53. E2 Regiochemistry Usually Zaitsev Formation of non-Zaitsev product:
When the base is a bulky base
t-BuO- is sterically hindered, does not remove more crowded H

54. E2 Regiochemistry Formation of non-Zaitsev product:
When anti-periplanar geometry cannot be achieved (substituted cyclohexanes)
Anti-periplanar = trans diaxial

55. cis-1-Chloro-2-isopropylcyclohexane

56. trans-1-Chloro-2-isopropylcyclohexane

57. The E1 Reaction Unimolecular elimination Rate = k [RX] Mechanism:
Multiple steps
Carbocation intermediate
Weak base is OK due to reactive R+ intermediate
Stereochemistry of RX not a factor due to R+ planarity
Regiochemistry is Zaitsev

58. 2-Methyl-2-chloropropane + CH3OH →
Products:
Mechanism:

59. E1 Reaction of Alcohols
Dehydration of an alcohol to form an alkene is also E1 mechanism
Reaction is reversible
Remove alkene as formed (distillation) to push to the right
Acid catalyst is needed
H3PO4 or H2SO4
Protonates –OH to make a better leaving group (H2O)
Example:

60. Zaitsev, unless bulky base or no anti-periplanar conformation
Summary of E2 vs. E1 E2 E1
Alkyl halide 1° 2° 3°
Base
Strong
Weak
Stereochemistry
Anti-periplanar
n/a
Regiochemistry
Zaitsev, unless bulky base or no anti-periplanar conformation
Zaitsev

61. Predict the elimination mechanism and products for the following reactions…

62. Outline In this chapter: Mechanisms of substitution
SN2
SN1
Mechanisms of elimination E2 E1
Substitution vs. elimination
SN2 or SN1 or E2 or E1

63. III. Substitution vs. Elimination
Given starting material and reagents
Predict mechanism and draw products
Remember regiochemistry and stereochemistry
Where do we start?
First, look at possible mechanisms for each RX structure
Then, compare reaction conditions for each mechanism

64. Possible Mechanisms
RX Structure
SN2
SN1 E2 E1
Methyl 1° 2° 3°

65. Reaction Conditions SN2 vs. SN1 E2 vs. E1 SN2 vs. E2 SN1 vs. E1
Good nucleophile and aprotic solvent favor SN2
Poor nucleophile and protic solvent favor SN1
E2 vs. E1
Strong base favors E2
Weak base favors E1
SN2 vs. E2
Good nucleophiles/weak bases favor SN2
Good nucleophiles/strong bases and 1° RX result in SN2 and E2
Good nucleophiles/strong bases and 2° RX result in E2
Bulky bases or branched RX favor E2
SN1 vs. E1
SN1 and E1 are both favored with weak nucleophiles/bases
Mixture of products from both SN1 vs. E1 will result anytime a unimolecular mechanism is predicted

66. The Magic Chart… Alkyl Halide Mechanism Conditions Methyl SN2
Only option 1°
Weak base/good nucleophile
Strong base, non-bulky (competes with E2) E2
Strong base, non-bulky (competes with SN2)
Bulky base
Branched RX 2°
Strong base
SN1/E1
Weak base/weak nucleophile 3°
Weak base
Strong bases (non-bulky): HO-, RO-, H2N-
Bulky base: t-BuO-
Weak base/good nucleophile: I-, CN-, CH3CO2-
Weak base/weak nucleophile: ROH, H2O, CH3CO2H (anything neutral)

67. Predict the substitution and/or elimination mechanism and draw products for the following reactions…